Glutamic acid is a neurotransmitter that mediates excitation transmission in the central nervous system. In addition to having various functions for neurotransmission, glutamic acid participates in many other important brain functions such as life and death, and differentiation and propagation of neurocytes, development of neurocytes and gliacytes, and plastic change in neurotransmission efficiency of matured or developed brains (for example, see Annual Review of Biophysics and Biomolecular Structure, Vol. 23. p. 319 (1994)).
Through pharmaceutical and molecular-biological studies, the glutamic acid receptor in the central nervous system of mammals is grouped into two, an ion channel-type glutamic acid receptor and a metabotropic glutamic acid receptor (hereinafter referred to as “mGluR”). The ion channel-type glutamic acid receptor comprises a complex of different subunit proteins, and it is an ion channel that is opened and shut through ligand bonding. On the other hand, mGluR conjugates with GTP-binding protein, and it acts through intracellular second messenger production or ion channel activity control via GTP-binding protein (for example, see Brain Research Reviews, Vol. 26, p. 230 (1998)).
In previous studies, it is reported that mGluR includes eight different subtypes of mGluR 1 to 8. These are grouped into three subgroups, depending on their amino acid sequence homology, signal transmission and pharmaceutical properties. Regarding their function for intracellular signal transmission, those of group I (mGluR 1 and 5) activate phospholipase C, and those of group II (mGluR 2 and 3) and group III (mGluR 4, 6, 7 and 8) act for adenylate cyclase activity control to thereby retard cyclic adenosine monophosphate (cAMP) accumulation through forskolin stimulation. Those of group II are selectively activated by LY354740 described in references (for example, Journal of Medicinal Chemistry, Vol. 42, p. 1027 (1999)); and those of group III are by L-AP4. Except mGluR 6 that specifically exists in the retina, the other receptors are expressed broadly in brain and nervous systems, each showing characteristic intracerabral distribution therein, and it is believed that these receptors individually play their own different physiological roles (for example, see Neurochemistry International, Vol. 24, p. 439 (1994) and European Journal of Pharmacology, Vol. 375, p. 277 (1999)).
Heretofore various reports are known relating to the role of mGluR in nervous systems. A part of the relationship between mGluR1 and various diseases is shown in the following (1) to (7).
(1) It is reported that a selective agonist for group I, 3,5-dihydroxyphenylglycine (hereinafter referred to as DHPG) causes convulsion when administered to a cerebral ventricle (for example, see Journal of Neuroscience Research, Vol. 51, p. 339 (1998)).
On the other hand, it is reported that, in a test with an mGluR1 selective antagonist, RS-1-aminoindane-1,5-dicarboxylic acid (hereinafter referred to as AIDA) shows a does-dependent anticonvulsive effect in a pentylenetetrazole-induced convulsive model generally used for evaluation of anticonvulsant potency (for example, see Neuropharmacology, Vol. 37, p. 1465 (1998)), and in addition to it, the compound shows an inhibitory effect to sound stimulation-induced convulsion in a genetic convulsive mouse and rat (for example, see European Journal of Pharmacology, Vol. 368, p. 17 (1999)). Further, it is reported that another selective antagonist, LY456236 shortens the convulsion continuance time and lowers the degree of convulsion in a tronsillar nucleus kindling rat known as a human convulsive model (for example, see Neuropharmacology, Vol. 43, p. 308 (2002)). The above suggest the anticonvulsive effect of mGluR1 antagonists.
(2) It is reported that, when DHPG is administered into the spinal cavity of a rat, it causes abnormal pain and pain supersensitivity to mechanical stimulation or causes pain supersensitivity to thermal stimulation (for example, see Neuroreport, Vol. 9, p. 1169 (1998)).
On the other hand, in investigations with antagonists, it is reported that, when AIDA is administered into a brain, it increases the pain threshold value (for example, see The Journal of Pharmacology & Experimental Therapeutics, Vol. 281, p. 721 (1997)), and that AIDA administration into the spinal cavity of continuous pain models such as a spinal cord damaged pain supersensitive model (for example, see Journal of Neurotrauma, Vol. 19, p. 23 (2002)) and an arthritic model (for example, see The Journal of Pharmacology & Experimental Therapeutics, Vol. 300, p. 149 (2002)) shows an analgesic effect. These informations suggest that the possibility that mGluR1 antagonists have an analgesic effect to not only continuous acute pain but also to inflammatory pain and chronic pain.
(3) The following reports suggest a protective effect for cerebral disorders such as cerebral infraction or transient cerebral ischemic attack. AIDA's effect of inhibiting delayed neuronal cell death in the hippocampus recognized in a transient whole brain ischemia-reperfusion model (for example, see Neuropharmacology, Vol. 38, p. 1607 (1999) and Neuroscience Letters, Vol. 293, p. 1 (2000)); cerebral cortical infraction volume reduction in a rat subdural hemorrhage model by an mGluR1 selective antagonist (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one (hereinafter referred to as “BAY36-7620”) (for example, see European Journal of Pharmacology, Vol. 428, p. 203 (2001)); and infraction whole volume reduction in a rat midbrain/cerebral artery ligated model by another selective antagonist R128494 (for example, see Neuropharmacology, Vol. 43, p. 295 (2002)).
(4) Administration of DHPG to a cerebral nucleus accumbens increases spontaneous motor activity, and its effect is similar to the reaction in administration of a dopamine receptor stimulant (for example, see European Journal of Neuroscience, Vol. 13, p. 2157 (2001)).
A description is given, saying that DHPG administration to a cerebral nucleus accumbens caused prepulse inhibition disorder recognized in experimental animal models and schizophrenics (for example, see Psychopharmacology, Vol. 141, p. 405 (1999)). These reactions caused by DHPG are all similar to the reaction recognized by a dopamine receptor stimulant such as typically apomorphine or a dopamine releasant such as amphetamine or methamphetamine. On the other hand, already-existing psychotropic drugs are considered to express their effect by inhibiting excessively excited dopamine nerves. Accordingly, the fact that DHPG showed a reaction similar to a dopamine stimulative action suggests the participation of mGluR1 and mGluR5 in nucleus accumbens in metal dysfunction, and its antagonist suggests a possibility of relieving the symptoms.
(5) In a Vogel-type conflict test with rats generally used in an evaluation system capable of detecting antianxiety effect of drugs, it is reported that a selective antagonist R128494 increased water drinking action accompanied by punishment (for example, see Neuropharmacology, Vol. 43, p. 295 (2002)). This result suggests a possibility that the mGluR1 antagonist has an antianxiety effect.
(6) The above-mentioned references (for example, European Journal of Pharmacology, Vol. 428, p. 203 (2001)) say that an mGluR1 selective antagonist, BAY36-7620 inhibits intracerebral self-stimulation promoted by an NMDA receptor antagonist MK-801. It has been clinically clarified that most NMDA receptor antagonists cause addiction, and the test system may be considered as a model that partly reflects MK-801 addiction. Accordingly, the above-mentioned reports suggest the possibility that mGluR1 veceptor selective antagonists may be a remedy for drug addiction.
(7) In a test where an extracellular potential is recorded using a rat brain slice that contains the subthalamic nucleus, DHPG local application showed increase in the action potential frequency (for example, see Brain Research, Vol. 766, p. 162 (1997)), and therefore, it is suggested that mGluR1 or mGluR5 may activate a subthalamic nucleus. It is well known that the subthalamic nucleus excitation is a characteristic of Parkinson's disease. Accordingly, there may be a possibility that an mGluR1 selective antagonist may be useful as a remedy for Parkinson's disease.
(8) Gastroesophageal reflux disease (GERD) is a most popular upper gastrointestinal tract disorder. The current drug therapy for it is for inhibition of gastric acid secretion or gastric acid neutralization in esophagus. Heretofore, it has been considered that the essential mechanism relating to reflux would be chronic stress depression of lower esophageal sphincter. However, it has become shown that almost all reflux episodes may be caused by relaxation occurring by the others than transient lower esophageal sphincter relaxations (TLESRs), or that is, swallowing (for example, see Gastroenterol Clin. North Am., Vol. 19, pp. 517-535 (1990)). Further, it has been known that gastric acid secretion in GERD patients is normal.
Lower esophageal sphincter (LES) may intermittently relax. As a result, during sphincter relaxation, one may temporarily lose a mechanical barrier and gastric juice may run into esophagus. This phenomenon is defined as “reflux”.
The term TLESRs indicating transient lower esophageal sphincter relaxations is defined according to Gastroenterology, Vol. 109(2), pp. 601-610 (1995).
The term “reflux” is defined as gastric juice capable of running into esophagus from stomach. This is because in that condition, one may temporarily lose its mechanical barrier. The term “GERD” indicating gastroesophageal reflux disease is defined according to Baillière's Clinical Gastroenterology, Vol. 14, pp. 759-774 (2000).
From the above-mentioned physiological and pathophysiological meanings, an mGluR1 antagonist is considered as useful for prevention or treatment of gastrointestinal disorders.
As compounds structurally relating to the compounds of formula (I), those of the following formula are described (for example, see WO91/09849):

However, in these compounds, an alkylamino group bonds to the pyridine ring bonding to the nitrogen atom of the piperazine ring; but in the compounds of the present invention, an alkanoylamino group or a 5- or 6-membered heteroaryl group bonds to the pyridine ring. Accordingly, they differ in their structures.
In addition, it is merely said that the compounds of the above-mentioned formulae are useful as a remedy for AIDS, and there is known neither description nor suggestion indicating that these compounds may act as an mGluR1 antagonist and may be useful as a remedy and/or a preventive for brain disorders such as convulsion, acute pain, inflammatory pain, chronic pain, cerebral infraction or transient cerebral ischemic attack, mental dysfunctions such as schizophrenia, and diseases such as anxiety, drug addiction, Parkinson's disease or gastrointestinal disorders.
In addition, there is known no reference showing that compounds of a formula (I):
(wherein the symbols have the same meanings as above) or their pharmaceutically acceptable salts may act as an mGluR1 antagonist; and there is known no description suggesting it.
Further, there is known no reference showing that the compounds of formula (I) or their pharmaceutically acceptable salts may be useful for treatment and/or prevention of brain disorders such as convulsion, acute pain, inflammatory pain, chronic pain, cerebral infraction or transient cerebral ischemic attack, mental dysfunctions such as schizophrenia, and diseases such as anxiety, drug addiction and/or Parkinson's disease; and there is known no description suggesting it.